ABSTRACT: Immunochemotherapy that combines a chemotherapeutic agent with an immune checkpoint blocker represents one of the most promising strategies for the treatment of various types of cancers including breast cancer. However, its success is limited by a number of issues including: a) the poor water solubility of the drug(s); and b) the challenge in simultaneous delivery of the two therapeutics to the tumors. We have developed a dual-functional, immunostimulatory nanomicellar carrier that was based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumor immune suppression. We showed that PEG-NLG alone was effective in enhancing T cell immune responses and exhibited significant antitumor activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG-NLG nanocarrier led to a significantly improved antitumor response in murine models of breast cancer. This application is focused on further improving this delivery system to facilitate drug release at tumor site. The potential of the improved nanocarrier in synergistic delivery of anticancer agents will then be investigated. Three specific aims will be pursued in this proposal. Aim 1 will develop an improved PEG-NLG-based delivery system with facilitated drug release following delivery to tumors. Aim 2 will examine the biodistribution and pharmacokinetics of the improved delivery system in murine breast cancer models. We will first define the stability of the improved delivery system in blood circulation. The efficiency of the system in delivery of PTX is then examined. Aim 3 will define the in vivo therapeutic effect of PTX formulated in the improved delivery system in murine models of breast cancer. The underlying mechanism for the synergistic antitumor activity will also be studied. Successful completion of this study will lead to the development of a novel strategy for improved breast cancer immunochemotherapy.